The AIDS crisis continues with ca. 40 million people infected by HIV-1, and 3 million deaths in 2004. AIDS Epidemic Update: December 2004: UNAIDS: Geneva, 2005. The therapeutic situation is challenged by rapid mutation of the virus to yield resistant strains. Anti-HIV drugs are normally given in combination, typically two nucleoside inhibitors of HIV-1 reverse transcriptase (NRTIs) and either a HIV protease inhibitor (PI) or a non-nucleoside RT inhibitor (NNRTI). HIV Medicine 2005; Hoffmann, C, Kamps, B. S., Eds.; Flying Publisher Paris, 2005. Long-term solutions include a vaccine, however, for those already infected, the current drugs do not systemically eliminate the virus, so they must be taken chronically. Many of the drugs require high dosages, which leads to compliance difficulties and costs that are only manageable in affluent nations. Patients often migrate among combinations, and long-term use of NRTIs and PIs can yield morphologic and metabolic complications including wasting and lipodystrophy. Pauwels, R. Curr. Opin. Pharmacol. 2004, 4, 437-446. The needs for new drugs and points of attack on HIV are profound. New drugs are expected to show enhanced activity against at least parts of the current spectrum of mutants.
Efforts have been aimed at the design of new NNRTIs. Three compounds in this class, nevirapine, delavirdine, and efavirenz, were approved by the FDA during 1996-1998. The first two succumb to many single point mutations in RT, and delavirdine is further debilitated by a high pill burden (400 mg bid). Efavirenz has an improved resistance profile and dosing (600 mg qd), though resistance still arises from common mutations including K103N and Y188L, and neurological side effects including dizziness and nightmares are frequent. Several NNRTIs with further improved resistance profiles such as DPC083, HBY097, and S-1153 (capravirine) stalled in clinical trials, while TMC125 (etravirine) continues on in spite of high dosage (900 mg bid).3 
Thus, there is much room for improvement, and we have pursued computer-aided design of new NNRTIs with simultaneous goals of enhanced performance against common RT mutants, high bioavailability, and facile synthesis. The approach features lead generation with the growing program BOMB, property prediction with QikProp, and assistance in lead optimization with Monte Carlo simulations using free-energy perturbation theory (MC/FEP). The present invention emanates from the results of that work.